Prostate cancer is the second leading cause of cancer death of American men. Metastatic prostate cancer is considered essentially incurable. In marked contrast, thyroid cancers can be effectively treated and, at times, cured even when widespread metastasis is present, because of the ability of the cells to concentrate iodine, making therapy with radioactive iodine possible and effective. The studies described in this proposal are aimed at transferring the gene for the thyroidal sodium-iodide symporter (NIS), the structure that is responsible for iodide trapping by thyroid cells, into prostate cancer cells. In addition, the potential role of this transfer as a means of gene therapy for metastatic prostate cancer is examined. The studies involve targeting expression of the NIS gene using prostate specific promoters in order to achieve prostate specific gene expression. Our preliminary studies have demonstrated the feasibility of this gene transfer in vitro and in vivo, in that high level and prostate specific iodide uptake has been established in LNCaP cell tumors in mice and those tumors have been successfully treated with 131I. The experiments outlined in this proposal will further examine the feasibility and efficacy of NIS gene transfer in vivo using mouse models, mechanisms of maximizing NIS protein expression and activity, and the cell killing effect of 131I in these models in vitro and in vivo. Further, our studies will examine the immune response within immunocompetent host mice following radioiodine killing of NIS transfected murine prostate tumors and the influence of that response upon the appearance and progression of native prostate cancer in transgenic mice (TRAMP), which naturally develop prostate cancer. Finally the proposal describes a phase I/II clinical trial of adenoviral mediated NIS gene transfer in patients with recurrent prostate cancer. Our studies, will serve to examine the potential of NIS gene transfer to prostate cancer as a method of therapy of metastatic disease and are the first so described. In addition, successful demonstration of radioiodine effect in our prostate cancer model will serve to stimulate interest in NIS as a therapeutic gene for other cancer types.